Paired Heavy and Light Chain Signatures Contribute to Potent SARS-CoV-2 Neutralization in Public Antibody Responses

Abstract

In briefBanach et al. report a SARS-CoV-2 neutralizing antibody along with genetic, structural, and functional features of public antibody responses targeting SARS-CoV-2. These data reveal how structural interactions with the SARS-CoV-2 receptor-binding domain correlate with viral neutralization and demonstrate the importance of native antibody heavy:light pairings in convergent antibody responses.

One-shot identification of SARS-CoV-2 S RBD escape mutants using yeast screening

“…This S RBD construct has its one native Nlinked glycan removed (N343Q) because the heavy N-linked mannosylation of S. cerevisiae could hamper anti-S RBD mAb recognition (Jigami, 2008). Cell-surface titrations of CR3022 IgG and nAb HKU-910-30 IgG yielded apparent dissociation constants comparable with reported in vitro results (Banach et al, 2021;Yuan et al, 2020a;Figure S2A). We then tested a panel of 11 additional anti-S RBD mAbs for binding to aglycosylated RBD.…”

“…Six mAbs completely ablated ACE2 binding, one mAb partially inhibited ACE2, and the remaining four did not prevent ACE2 binding (Figure 1C). An inverse correlation was observed between the previously determined neutralization potency of the antibody (Banach et al, 2021;Yuan et al, 2020a) and the fluorescence signal increase in the competition assay (Figure 1C). We conclude from these experiments that, excluding the S309 epitope, the aglycosylated S RBD platform faithfully recapitulates binding interactions of nAbs with S RBD (Rogers et al, 2020).…”

“…We had previously developed an aglycosylated S-RBD YSD platform (S RBD(333-537)-N343Q) from the original Wuhan-Hu-1 strain (Banach et al, 2021) that can bind specifically to ACE2 (Figure 1A). This S RBD construct has its one native Nlinked glycan removed (N343Q) because the heavy N-linked mannosylation of S. cerevisiae could hamper anti-S RBD mAb recognition (Jigami, 2008).…”

“…Dozens of studies have reported the structural, epitopic, and functional landscape of non-neutralizing monoclonal antibodies and neutralizing antibodies (nAbs) targeting trimeric S (Banach et al, 2021;Rogers et al, 2020;Yuan et al, 2020a). A prophetic understanding of the mutations on S that could evade antibody recognition would enable development of better vaccine boosters and monoclonal antibody therapies.…”

Structural basis for accommodation of emerging B.1.351 and B.1.1.7 variants by two potent SARS-CoV-2 neutralizing antibodies

“…Recent studies have shown that some of these new variants impede the function of some SARS-CoV-2 neutralizing antibodies, with most NTD-directed neutralizing antibodies showing a near complete loss of potency against either the B.1.351 or B.1.1.7 strains ( Wang et al., 2021b ; Wibmer et al., 2021 ). With respect to RBD-directed antibodies, however, while the most prevalent classes of multi-donor RBD-directed antibodies, originating from the VH3-53/66 and VH1-2 genes ( Banach et al, 2021 ; Rapp et al., 2021 ; Yuan et al., 2020 ), are generally inhibited by mutations in RBD (K417N and N501Y for VH3-53/66 class antibodies and E484K for VH1-2 class antibodies) ( Wang et al., 2021b ). Fortunately, many RBD-directed antibodies not from these frequent classes retain their activity.…”